Title: In Vivo Mechanisms of Integrated G protein Signaling Regulation by RGS Proteins Project Abstract G protein signaling is involved in the function of many biological systems including neural, humoral, autocrine, and paracrine systems that maintain physiological homeostasis. Defects that result in increased G protein signaling have been implicated in many pathophysiological disorders, most notably hypertension and heart disease. Therefore, efforts that increase the understanding of G protein regulation are a major approach to understand disease etiology and develop more effective treatments for cardiovascular disorders. Regulators of G protein signaling (RGS) regulate G protein signaling by acting as GTPase-activating proteins (GAPs), accelerating GTP hydrolysis to terminate G protein activity. Many RGS proteins, including all members of the R4/B subfamily, are highly expressed in organ systems involved in the control of blood pressure and cardiac function. However, it is not known how the functions of multiple RGS proteins are integrated or whether they work interdependently to control G protein signaling in the cardiovascular system to maintain homeostasis. To address these questions, we have generated mice lacking both RGS2 and 5 (Rgs2/5 dbKO) concurrently. Although these mice are viable, they develop severe hypertension, have unprovoked cardiac hypertrophy, and the male mice are extremely sensitive to surgery-induced stress, causing death. The overall goals of the proposal are to determine the mechanisms that mediate augmented pathological phenotypes and death in Rgs2/5 dbKO mice, and to determine whether regulation of G protein signaling by RGS2 and 5 are coordinated to maintain normal cardiovascular physiology. We are poised to address the specific aims in this project by assembling all the necessary tools and expertise in molecular and cellular biology, echocardiography, biochemistry, and integrative physiology. Findings from this work will greatly enhance our understanding of G protein signaling regulation by RGS proteins in the cardiovascular system and elsewhere, thereby making a broad impact in the field.